Mesenchymal stromal cells mitigate liver damage after extended resection in the pig by modulating thrombospondin-1/TGF-β

Abstract

Post-surgery liver failure is a serious complication for patients after extended partial hepatectomies (ePHx). Previously, we demonstrated in the pig model that transplantation of mesenchymal stromal cells (MSC) improved circulatory maintenance and supported multi-organ functions after 70% liver resection. Mechanisms behind the beneficial MSC effects remained unknown. Here we performed 70% liver resection in pigs with and without MSC treatment, and animals were monitored for 24 h post surgery. Gene expression profiles were determined in the lung and liver. Bioinformatics analysis predicted organ-independent MSC targets, importantly a role for thrombospondin-1 linked to transforming growth factor-β (TGF-β) and downstream signaling towards providing epithelial plasticity and epithelial-mesenchymal transition (EMT). This prediction was supported histologically and mechanistically, the latter with primary hepatocyte cell cultures. MSC attenuated the surgery-induced increase of tissue damage, of thrombospondin-1 and TGF-β, as well as of epithelial plasticity in both the liver and lung. This suggests that MSC ameliorated surgery-induced hepatocellular stress and EMT, thus supporting epithelial integrity and facilitating regeneration. MSC-derived soluble factor(s) did not directly interfere with intracellular TGF-β signaling, but inhibited thrombospondin-1 secretion from thrombocytes and non-parenchymal liver cells, therewith obviously reducing the availability of active TGF-β.

Human Mesenchymal Stromal Cells Resolve Lipid Load in High Fat Diet-Induced Non-Alcoholic Steatohepatitis in Mice by Mitochondria Donation

“…MSC treatment preserves epithelial integrity. As shown recently, MSC did not directly interfere with epithelial adhesion contacts, but rather indirectly affected pathways promoting epithelial–mesenchymal transitions such as thrombospondin-1/TGFβ-1 [ 48 ]. THBS1 is not affected by MSC treatment in the present study, suggesting other pathways being involved and corroborating the assumption that improvement of epithelial integrity and hepatocyte functions is not the cause, but rather the consequence of MSC action.…”

“…Thrombospondin-1 (THBS1) is elevated in fibrotic liver diseases [ 45 ] including NASH [ 46 ], and THBS1 from macrophages is assumed to foster NASH in the context of obesity [ 47 ]. Likewise, thrombocyte-derived THBS1 promotes acute tissue damage after extended liver surgery [ 48 ], altogether demonstrating that blood-borne cellular mechanisms drive the pathogenesis of NASH. In mice fed the high fat diet, THBS1 was elevated in the liver as verified by fluorescent immunohistochemistry ( Supplementary Figure S3A ).…”

Clinical Application of Induced Hepatocyte-like Cells Produced from Mesenchymal Stromal Cells: A Literature Review

“…Bruno et al were able to also show reductions in fibrosis, as well as reductions in TGF beta, a key cytokine involved in fibrosis, as well as reductions in collagen and smooth muscle actin expression, which is also suggestive of reduced fibrogenic processes [42]. These results were supported by reductions in TGF beta plasma levels observed early after mHep administration in pigs [46].…”

“…Therapeutic utility of mHeps has been demonstrated in a variety of different types of liver disease (Table 2). Several studies have demonstrated the engraftment of these mHeps in rodent models [19,27,28,36,[39][40][41][42][43][44][45] and pigs [46]. The efficiency of engraftment has generally not been reported, although Aurich et al presented data indicating that upwards of 20% of mouse livers were composed of mHeps at 10 weeks [41].…”

“…Five of the studies in Table 2 have moved their processes toward the commercial scale. Nickel et al scaled up the production of mHeps from porcine bone marrow MSCs sufficiently to dose adult pigs (25-30 kg) with 1 × 10 8 cells, which is in the range anticipated for human doses [46]. Quality control parameters measured include Western blot analyses of livers for phosphoenolpyruvate carboxykinase 1, glutamine synthase, cytochrome P450 1A1, and cytochrome P450 3A4, as well as glycogen storage by PAS stain.…”